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You searched for +publisher:"Harvard University" +contributor:("Liberles, Stephen"). Showing records 1 – 3 of 3 total matches.

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Harvard University

1. Nguyen, Anthony Tuan. A Novel Program of Ubiquitination Remodels the Erythroid Proteome During Terminal Differentiation.

Degree: PhD, 2016, Harvard University

The ubiquitin-proteasome system was initially discovered in reticulocytes, which undergo massive and rapid proteome remodeling. During terminal differentiation, hundreds of generic constituents of the cell undergo programmed elimination. However, the mechanisms that drive the turnover of normally stable proteins remain largely unknown. Two decades ago, an unusually large ubiquitin-conjugating enzyme, Ube2O, was found to be strongly and specifically upregulated in terminally differentiating reticulocytes, contemporaneously with the induction of globin. A null mutation in the murine Ube2O gene, known as hem9, resulted in a hypochromic, microcytic anemia, suggesting that Ube2O may be a major ubiquitinating factor in erythropoiesis. To understand the role of Ube2O in terminal differentiation, we first found that all major low molecular weight ubiquitin-protein conjugate bands are greatly reduced in levels in hem9 reticulocytes. When null reticulocyte lysates were treated with recombinant Ube2O, ribosomal proteins were overwhelmingly the major class of targets. Accordingly, hem9 reticulocytes have elevated ribosomal protein levels and 80S ribosomes. This phenotype of elevated ribosome abundance was accounted for by a defect in the elimination of ribosomes. Furthermore, overexpression of Ube2O was sufficient to drive ribosomal degradation in non-erythroid 293 cells. Quantitative mass spectrometry on these cells confirmed the destabilization of ribosomal proteins and indicated that Ube2O has a specific, yet broad ubiquitination program. Interestingly, the hem9 defect was phenocopied by treating wild-type reticulocytes with proteasome inhibitors. To confirm this finding, we reconstituted the degradation of ribosomal proteins in a cell-free reticulocyte lysate system. We also reconstituted the ubiquitination of purified ribosomes by recombinant Ube2O in vitro, and the degradation of several specific ribosomal proteins with purified proteasomes. Next, we found that the initiation factor eIF2α is hyperphosphorylated in hem9 reticulocytes, suggesting a global inhibition of protein synthesis. This was independent of HRI, a dominant regulator of translation in reticulocytes; instead, another eIF2α kinase, GCN2 was activated in the null mutant. Consistent with these findings, null reticulocytes were deficient in free amino acids, a phenotype that was recapitulated by proteasome inhibition. In summary, Ube2O selectively ubiquitinates ribosomal proteins and targets them to the proteasome for degradation, thus playing a central role during terminal erythroid differentiation.

Medical Sciences

Advisors/Committee Members: Liberles, Stephen (committee member), Goldberg, Alfred (committee member), Lodish, Harvey (committee member).

Subjects/Keywords: Biology, Cell; Biology, Molecular

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Nguyen, A. T. (2016). A Novel Program of Ubiquitination Remodels the Erythroid Proteome During Terminal Differentiation. (Doctoral Dissertation). Harvard University. Retrieved from http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493556

Chicago Manual of Style (16th Edition):

Nguyen, Anthony Tuan. “A Novel Program of Ubiquitination Remodels the Erythroid Proteome During Terminal Differentiation.” 2016. Doctoral Dissertation, Harvard University. Accessed October 24, 2020. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493556.

MLA Handbook (7th Edition):

Nguyen, Anthony Tuan. “A Novel Program of Ubiquitination Remodels the Erythroid Proteome During Terminal Differentiation.” 2016. Web. 24 Oct 2020.

Vancouver:

Nguyen AT. A Novel Program of Ubiquitination Remodels the Erythroid Proteome During Terminal Differentiation. [Internet] [Doctoral dissertation]. Harvard University; 2016. [cited 2020 Oct 24]. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493556.

Council of Science Editors:

Nguyen AT. A Novel Program of Ubiquitination Remodels the Erythroid Proteome During Terminal Differentiation. [Doctoral Dissertation]. Harvard University; 2016. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493556


Harvard University

2. Pashkovski, Stan. A Chemical Odor Map in Cortex.

Degree: PhD, 2017, Harvard University

Odorous molecules trigger specific percepts. Appropriate assignment of odorants to corresponding percepts relies on the brain’s ability to both discriminate distinct odorants, as well as generalize odorants that share chemical features. Although odorants evoke correlated activity across receptor expressing neurons in the olfactory epithelium and glomeruli residing in the olfactory bulb, it is unclear how the chemical attributes of odors are encoded in cortex to support both discrimination and generalization. To address this question, we have developed a preparation that allows us to monitor odor representations in awake mice across cortical layers in the main region of the brain devoted to olfactory processing, the Piriform Cortex (PCx). Using sets of odorants rationally designed to tile different regions of chemical odor space, we demonstrate that responses of neural ensembles in both Layer II (LII) and Layer III (LIII) of PCx preserve information about the physicochemical relationships between odor molecules in a manner conserved across individual mice. LII and LIII differ in terms of their correlation structure, reliability, odor sensitivity, and odor preferences, suggesting parallel representational strategies optimized for odor discrimination and generalization. These findings suggest that PCx harbors an invariant relational map of odorant space. The differential expression of this map across distinct cortical layers further suggests complementary contributions to perception and odor-guided behavior.

Biology, Molecular and Cellular

Advisors/Committee Members: Assad, John (committee member), Liberles, Stephen (committee member), Mainland, Joel (committee member).

Subjects/Keywords: piriform cortex; olfaction

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Pashkovski, S. (2017). A Chemical Odor Map in Cortex. (Doctoral Dissertation). Harvard University. Retrieved from http://nrs.harvard.edu/urn-3:HUL.InstRepos:42061487

Chicago Manual of Style (16th Edition):

Pashkovski, Stan. “A Chemical Odor Map in Cortex.” 2017. Doctoral Dissertation, Harvard University. Accessed October 24, 2020. http://nrs.harvard.edu/urn-3:HUL.InstRepos:42061487.

MLA Handbook (7th Edition):

Pashkovski, Stan. “A Chemical Odor Map in Cortex.” 2017. Web. 24 Oct 2020.

Vancouver:

Pashkovski S. A Chemical Odor Map in Cortex. [Internet] [Doctoral dissertation]. Harvard University; 2017. [cited 2020 Oct 24]. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:42061487.

Council of Science Editors:

Pashkovski S. A Chemical Odor Map in Cortex. [Doctoral Dissertation]. Harvard University; 2017. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:42061487


Harvard University

3. Baldwin, Maude Wheeler. Evolution of sweet taste perception in hummingbirds.

Degree: PhD, 2015, Harvard University

Mammals have three members of the small taste receptor gene family responsible for the perception of sweet and savory tastes: two genes (T1R2 and T1R3) comprise the canonical sweet receptor, and a third gene, T1R1, acts with T1R3 to make the savory receptor. Here, in a joint effort with a team of international collaborators, we show that even though birds are missing the taste receptor gene (T1R2) required by other vertebrates to perceive carbohydrates and sweeteners, hummingbirds still detect sugars—but in a novel way. This project spanned multiple fields and field sites, integrating taste tests on wild birds, behavioral analysis of captive animals, bioinformatics, receptor cloning, and cell-based functional assays. The first published avian genome, that of the chicken, revealed a surprising lack of T1R2. Chickens are sweet-insensitive: however, many nectar-feeding birds appear highly attuned to sugars like sucrose, fructose and glucose. Our initial field experiments with a panel of artificial sweeteners as well as high-speed filming and choice tests on captive birds indicated a rapid response to sugars rather than a post-ingestive metabolic sensing of caloric value. As the response appeared sensory, we pursued a candidate gene approach to search for possible taste receptors, and cloned T1R taste receptors from chickens, hummingbirds, and swifts. By analyzing genomes from an additional 10 birds and an alligator, we documented widespread absence of T1R2 and identified signatures of positive selection in the remaining hummingbird T1Rs. Together with Dr. Yasuka Toda at the University of Tokyo, we were able to test the function of these receptors in cell culture. We used a cell-based luminescence assay to measure functional responses. As expected, chicken and swift receptors responded to amino acids, but, surprisingly, the umami receptor in hummingbirds had acquired a new function and was now sensitive to carbohydrates as well. Chimeric studies of receptors containing hummingbird and chicken sequence identified 19 mutations involved in this functional change: since divergence from swifts, the umami receptor underwent extensive re-modeling. Further behavioral tests with wild hummingbirds revealed that most agonists from the cell-based assay were appetitive, while artificial sweeteners which did not activate the receptors were not preferred—a concordance between in vivo and in vitro studies that indicates that this re-purposed receptor guides hummingbird taste behavior. Diet shifts have profound physiological effects and evolutionary ramifications: the radiation of hummingbirds is likely due, at least in part, to their ability to colonize an empty niche. However, much remains to be learned about the roles of taste in changes in diet, and the causes and effects of shifts in diet and perception are often unclear. For instance, birds appear to have lost T1R2 early in their evolutionary history. As they are the descendants of carnivorous dinosaurs, birds may have experienced relaxed selection on the sweet receptor… Advisors/Committee Members: Edwards, Scott V. xmlui.authority.confidence.description.cf_ambiguous (advisor), Hoekstra, Hopi E. (committee member), Pierce, Naomi E. (committee member), Dulac, Catherine (committee member), Liberles, Stephen (committee member).

Subjects/Keywords: Biology, General; Biology, Molecular; Biology, Animal Physiology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Baldwin, M. W. (2015). Evolution of sweet taste perception in hummingbirds. (Doctoral Dissertation). Harvard University. Retrieved from http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467228

Chicago Manual of Style (16th Edition):

Baldwin, Maude Wheeler. “Evolution of sweet taste perception in hummingbirds.” 2015. Doctoral Dissertation, Harvard University. Accessed October 24, 2020. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467228.

MLA Handbook (7th Edition):

Baldwin, Maude Wheeler. “Evolution of sweet taste perception in hummingbirds.” 2015. Web. 24 Oct 2020.

Vancouver:

Baldwin MW. Evolution of sweet taste perception in hummingbirds. [Internet] [Doctoral dissertation]. Harvard University; 2015. [cited 2020 Oct 24]. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467228.

Council of Science Editors:

Baldwin MW. Evolution of sweet taste perception in hummingbirds. [Doctoral Dissertation]. Harvard University; 2015. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467228

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